ABSTRACT PROJECT SUMMARY These are exciting times as a blood test for traumatic brain injury is on the horizon. This R01 competitive renewal is a large scale validation study that will extend the work we have done on serum biomarkers in adults to children and youth, previously understudied groups. This proposal will systematically validate the diagnostic and prognostic ability of well-studied serum protein biomarkers and promising microRNA serum biomarkers in children and youth with mild traumatic brain injury (MTBI) and concussion. The biomarkers being proposed here have been studied in adults in data published by our group. Moreover, we will be examining promising microRNA biomarkers that we have evaluated in recently published pilot work. Patients will be enrolled from the emergency departments of adult and pediatric Level 1 Trauma Centers. Our first aim is will assess the brain-specificity of candidate biomarkers in determining presence of MTBI/concussion versus other traumatic injuries and head trauma without symptoms, as well as determining baseline levels by age and gender in uninjured children and youth. Being able to distinguish someone with and without a concussion would be so helpful, especially in children who cannot talk yet or with conditions such as autism spectrum disorders who cannot express themselves. Our second aim will assess the diagnostic performance of candidate biomarkers in detecting critical injuries such as intracranial lesions on CT scan and acute neurological complications and will compare biomarker performance to validated clinical decision rules. This could potentially help reduce the number of CT scans done on children and reduce their exposure to ionizing radiation. Our third and final aim will assess the prognostic utility of serially measured biomarkers over six months in determining impairment or problems functioning. It will also help us understand the pattern of biomarker release over time in children and youth as it relates to recovery from injury. The goal of this research is to improve the clinical care of children and youth with MTBI and concussion by early recognition of injury and clinically validating a panel of blood- based markers (blood test) that could be used by clinicians in the acute, subacute, and chronic phases of injury to determine the need for diagnostic imaging (CT or MRI), acute neurological complications, specialized rehabilitation, or long-term risk for neurocognitive impairment. Ultimately, we hope the results of the proposal will change clinical practice by providing medical professional with more sensitive tools to detect brain injury and help patients and their families better understand their injury and recovery.